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Clinical efficacy of ex vivo HSC gene therapy has been achieved in certain clinical trials for children with X-linked severe combined immunodeficiency (X-SCID) and adenosine deaminase (ADA)-deficient SCID using ex vivo HSC gene transfer. However, the general clinical application of this approach is still impeded by many difficulties such as low levels of HSCs transduction, inadequate engraftment of transduced stem cells, silencing of transgene expression, as well as the risk of insertional oncogenesis. Our attempts to overcome these problems involve optimization of transduction protocol, introduction of potential in vivo selection and preconditioning of recipients, as well as alternation of target cells and vector system. For example, in vivo selection of genetically modified cells is an attractive approach that may compensate for relatively low gene transfer efficiency achievable in clinical trials. The Pan Lab has investigated the feasibility of MGMTP140K-mediated selection in primary hepatocytes from MPS I mouse model, and provided “proof of concept” to the prospect of co-selection for hepatocytes and HSC using BG / BCNU treatment.
Targeted gene transfer and gene expression, which are of interest to our research, have the potential to provide efficient transgene expression in a more defined manner with relatively less genotoxicity (i.e., less disturbing of the genome). More recently, as an effort to reduce the risk of activating oncogenes in HSCs and their progeny following gene transfer, Dao Pan’s group worked on restricting transgene expression to maturing erythroid cells yet taking advantage of the robust protein synthesis machinery in developing red blood cells (RBC). This study, reported in Proceedings of the National Academy of Sciences and highlighted in Molecular Therapy, was the first to demonstrate that maturing erythroid cells could be “adapted” for producing and releasing lysosomal enzyme into the circulation. Moreover, supraphysiological levels of lysosomal enzyme could be achieved continuously in serum of enzyme-deficient mice with moderate gene transfer efficiency, leading to therapeutic benefits in both viscera organs and the CNS in disease mouse model. This approach offers a promising potential to achieve high efficacy without the risk of high-copy numbers per cell, thereby reducing the risk of oncogenic adverse events. This approach opens a paradigm for using RBC precursors as a depot to develop a safer and more efficient treatment for systemic long-term delivery of non-secreted proteins with therapeutic CNS benefits in the treatment of other LSDs.
Dr. Dao Pan, PhD
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